Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity. For example, cereblon (CRBN) interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 in which the proteins recognized by CRBN are ubiquitinated and degraded by proteasomes. Various immunomodulatory drugs (IMiDs), e.g. thalidomide and lenalidomide, binds to CRBN and modulate CRBN's role in the ubiquitination and degradation of protein factors involved in maintaining regular cellular function.
Harnessing the ubiquitin-proteasome pathway for therapeutic intervention has received significant interest from the scientific community. The publication by Gosink et al. (Proc. Natl. Acad. Sci. USA 1995, 92, 9117-9121) titled “Redirecting the Specificity of Ubiquitination by Modifying Ubiquitin-Conjugating Enzymes” showed proof of concept in vitro that engineered peptides can selectively direct ubiquitination to intracellular proteins. The publication by Nawaz et al. (Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 1858-1862) titled “Proteasome-Dependent Degradation of the Human Estrogen Receptor” describes ER degradation as a target for the ubiquitin-proteasome pathway. The publication by Zhou et al. (Mol. Cell 2000, 6, 751-756) titled “Harnessing the Ubiquitination Machinery to Target the Degradation of Specific Cellular Proteins” demonstrated an engineered receptor capable of directing ubiquitination in mammalian and yeast cells.
U.S. Pat. No. 6,306,663 filed in 1999 assigned to Proteinex, Inc., titled “Controlling Protein Levels in Eucaryotic Organisms” appears to be the first patent disclosure of ubiquitinating molecules that incorporate a ubiquitination recognition element and a target protein recognition element.
U.S. Pat. No. 7,041,298 titled “Proteolysis Targeting Chimeric Pharmaceutical” was filed in September 2000 by Deshales et al. and granted in May 2006. The publication by Sakamoto et al. (Proc. Natl. Acad. Sci. USA 2001, 98, 8554-8559) titled “Protacs: Chimeric Molecules That Target Proteins to the Skp 1-Cullin-F Box Complex for Ubiquitination and Degradation” describes a “PROTAC” consisting of a small molecule binder of MAP-AP-2 linked to a peptide capable of binding the F-box protein (3-TRCP, the disclosure of which is also provided in the corresponding U.S. Pat. No. 7,041,298. The publication by Sakamoto et al. (Mol. Cell. Proteomics 2003, 2, 1350-1358) titled “Development of Protacs to Target Cancer-Promoting Proteins for Ubiquitination and Degradation” describes an analogous PROTAC (PROTAC2) that instead of degrading MAP-AP-2, degrades estrogen and androgen receptors. The publication by Schneekloth et al. (J. Am. Chem. Soc. 2004, 126, 3748-3754) titled “Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation” describes an analogous degradation agent (PROTAC3) that targets the FK506 binding protein (FKBP12) and shows that both PROTAC2 and PROTAC3 hit their respective targets using green fluorescent protein (GFP) imaging. The publication by Schneekloth et al. (ChemBioChem 2005, 6, 40-46) titled “Chemical Approaches to Controlling Intracellular Protein Degradation” described the state of the field at the time. The publication by Schneekloth et al. (Bioorg. Med. Chem. Lett. 2008, 18, 5904-5908) titled “Targeted Intracellular Protein Degradation Induced by a Small Molecule: En Route to Chemical Proteomics” describes a degradation agent that consists of two small molecules linked by PEG that in vivo degrades the androgen receptor by concurrently binding the androgen receptor and Ubiquitin E3 ligase. WO 2013/170147 filed by Crews et al. titled “Compounds Useful for Promoting Protein Degradation and Methods Using Same” describes compounds comprising a protein degradation moiety covalently bound to a linker, wherein the C log P of the compound is equal to or higher than 1.5. A review by Buckley et al. (Angew. Chem. Int. Ed. Engl. 2014, 53, 2312-2330) titled “Small-Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System” describes a variety of publications. WO 2015/160845 assigned to Arvinas Inc. titled “Imide Based Modulators of Proteolysis and Associated methods of Use” describes the use of degradation compounds including thalidomide to utilize cereblon as the E3 ligase protein. The publication by Lu et al. (Chem. Biol. 2015, 22, 755-763) titled “Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target Brd4” describes thalidomide based degradation compounds useful for degrading BRD4. Additional publications include Bondeson et al. (Nat. Chem. Biol. 2015, 11, 611-617) titled “Catalytic in Vivo Protein Knockdown by Small-Molecule Protacs”; Gustafson et al. (Angewandte Chemie, International Edition in English 2015, 54, 9659-9662) titled “Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging”; Buckley et al. (J. Am. Chem. Soc. 2012, 134, 4465-4468) titled “Targeting the Von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt the Vhl/Hif-1alpha Interaction”; U.S. 2016/0058872 assigned to Arvinas Inc. titled “Imide Based Modulators of Proteolysis and Associated Methods of Use”; U.S. 2016/0045607 assigned to Arvinas Inc. titled “Estrogen-related Receptor Alpha Based PROTAC Compounds and Associated Methods of Use”; U.S. 2014/0356322 assigned to Yale University, GlaxoSmithKline, and Cambridge Enterprise Limited University of Cambridge titled “Compounds and Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase”; Lai et al. (Angewandte Chemie, International Edition in English 2016, 55, 807-810) titled “Modular Protac Design for the Degradation of Oncogenic Bcr-Abl”; and Toure et al. (Angew. Chem. Int. Ed. 2016, 55, 1966-1973) titled “Small-Molecule Protacs: New Approaches to Protein Degradation”. See also US 2016/0176916, US 2016/0235730, US 2016/0235731, US 2016/0243247, WO 2016/105518, WO 2016/077380, WO2016/105518, WO 2016/077375, WO2017/007612, and WO2017/024317.
It was discovered and reported in 2010 that thalidomide binds to cereblon (see Ito et al. (Science 2010, 327, 1345-1350) titled “Identification of a Primary Target of Thalidomide Teratogenicity” and Fischer et al. (Nature 2014, 512, 49-53) titled “Structure of the Ddb1-Crbn E3 Ubiquitin Ligase in Complex with Thalidomide”). Itoh et al. also described a small molecule linked to a peptide that utilizes E3 ubiquitin ligase to degrade retinoic acid-binding proteins. (See J. Am. Chem. Soc. 2010, 132, 5820-5826 titled “Protein Knockdown Using Methyl Bestatin-Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins”).
The object of the present invention is to provide bifunctional compounds and compositions for the treatment of serious diseases, including kinase mediated disorders.